E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypovolaemia in Severe Sepsis / Septic Shock |
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E.1.1.1 | Medical condition in easily understood language |
Volume replacement in Severe Sepsis / Septic Shock |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Investigate the efficacy of early goal directed fluid management of a combination of a gelatin and crystalloid regime in comparison to a pure crystalloid regime in achieving haemodynamic stability (HDS) in patients with severe sepsis / septic shock. |
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E.2.2 | Secondary objectives of the trial |
Investigation of safety and efficacy parameters of the applied fluid regimes. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female patients ≥ 18 and ≤ 85 years of age
• Women of child bearing potential must test negative on standard pregnancy test (urine or serum)
• Patients with body weight ≥ 55 kg and ≤ 140 kg and body mass index (BMI) ≥ 18 kg/m2 and ≤ 35 kg/m2
• Patients diagnosed severe sepsis / septic shock (refer to section 7.2.1 for definitions) at admission on ICU who can be enrolled within 90 min after admission OR patients diagnosed severe sepsis / septic shock during ICU stay who can be enrolled within 90 min after diagnosis
• Patients already treated with antibiotic therapy (prior to randomization)
• Patient who are fluid responsive. Fluid responsiveness is defined as increase of at least 10% in mean arterial pressure (MAP) after PLR
• Signed informed consent by patient, legal representative or authorized person or deferred consent |
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E.4 | Principal exclusion criteria |
• Administration of artificial colloids within the 24 h prior to randomization
• Death expected within the next 48 h
• Patients whose medical condition does preclude the PLR manoeuvre
• Patients for whom the need of pressure infusions are expected
• Requirement for renal support (either continuous or discontinuous techniques, including intermittent haemodialysis, haemofiltration and haemodiafiltration)
• Patients receiving heparin / anticoagulation therapy
• Burned patients
• Chronic renal failure with oliguria or anuria
• Severe general oedema
• Severe cardiac insufficiency (defined as NYHA ≥ III)
• Hypersensitivity to the active substance or ingredients of the IPs
• Hypervolaemia / hyperhydration
• Hyperkalaemia (requiring medical treatment)
• Hypercalcaemia (requiring medical treatment)
• Metabolic alkalosis
• Simultaneous participation in another interventional clinical trial (drugs or medical devices studies) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time until first / initial HDS is achieved (in minutes).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time measurement will start with first administration of IPs and will be continued until first HDS is achieved. |
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E.5.2 | Secondary end point(s) |
• Safety
-Renal function
Serum creatinine (SCr)
Serum blood urea nitrogen (BUN)
Urine creatinine
Estimated glomerular filtration rate (eGFR)
Creatinine clearance
Need and indication of renal replacement therapy (RRT)
Urine output
Kidney Disease Improving Global Outcome (KDIGO) score
-Coagulation
Prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
International norm ratio (INR)
ROTEM (optional)
-Hepatic function
Bilirubin
Adverse Events
(Serious) adverse events ((S)AEs) / reactions ((S)ARs)
-Other
Number of red blood cell (RBC) units
Number of fresh frozen plasma (FFP) units
Number of other blood products
Vasopressor therapy
Inotropic therapy
- Efficacy
Fluid administration according to the volume algorithm
Volume needed to achieve first / initial HDS
Total volume until 48 h after randomization
Administered bottles
Additional administered crystalloid solutions for further volume treatment
Drug and volume
Fluid balance
Fluid intake
Fluid output
Fluid balance
Haemodynamics
Volume responsiveness upon passive leg raising (PLR) or exogenous fluid challenge
Haemodynamic readings as required by the volume algorithm and haemodynamics from 48 h after randomization until ICU discharge or day 28, whatever occurs first
-Tissue oxygenation and acid base balance
Arterial blood gas analyses (BGA)
Serum electrolytes
Base excess (BE)
Lactate / lactate decrease
Phosphate
Magnesium
Central venous BGA
Arterial oxygen content
Oxygen delivery
Perfusion index (optional)
pCO2 gap (optional)
• Outcome
Length of stay (LOS) in the intensive care unit (ICU)
Hospital LOS
Days on RRT
Number of infection free days
Number of antibiotic free days
Number of ventilator free days
Number of vasopressor free days
-Follow-up
Last available SCr (day 28)
Colloid therapy (day 28)
Mortality & cause of death (if applicable) (day 28 & day 90)
Health-related quality of life (HRQoL) (day 90)
New RRT / kidney disease (day 90)
-Other variables
Demographic data
Age
Gender
Height
Weight
Race
Type of patient (e.g. trauma patient, surgical patient)
Anamnesis
APACHE II, SAPS II & SOFA score
Temperature
Fluid input in the 24 h prior to randomization
Origin of sepsis
Procalcitonin (optional)
Causative organism of infection
Medical history
Concomitant medication
Antibiotic therapy
Nephrotoxic therapy
Contrast agents
Anticoagulation therapy
Study termination
Time points of evaluation:
At random.: Demographics, Anamnesis, Med. history; At random. until day 7 (once daily): eGFR, KDIGO; From random. to 48 hrs after random. (cont.): Fluid admin. acc. algorithm, Vol. needed to achieve first / initial HDS, Total volume, Vol. responsiveness upon PLR /exog. fluid challenge, Haemodyn. ; At ICU/hospital discharge: LOS; At random. to ICU discharge/day 28 (once daily): Renal function, Coagulation, Hepatic funct., APACHE II, SAPS II & SOFA score, Temp.; From random.to ICU discharge/day 28 (once daily): RRT need, Urine output, Days on RRT, Con. Med.; From random. to ICU discharge/day 28 (cont.): (S)AEs / (S)ARs, Number of blood product units, Vasopressor/inotropic therapy, Add. admin. cryst. solutions, Fluid balance; From random. until ICU discharge/day 28: within the first 6 hrs every 2 hrs, then every 12 hrs; from 48 hrs until ICU discharge/day 28 (once daily): Tissue oxygenat. /acid base balance, S. electrolytes; Cumul.: infection/antibiotic/ventilator/vasopressor free days; Day 28: Last available SCr, Colloid therapy, Day 28 + 90: Mortality & cause of death (if applic.), Day 90: HRQoL, New RRT/kidney disease |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Completion of last follow up of last patient. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |